ABSTRACT: The Pre-Clinical Models of Acute Lung Injury Core (Core C) is designed to provide PPG investigators with rigorously defined and reproducible murine models of acute respiratory distress syndrome (ARDS) and ventilation-induced lung injury (VILI). The Core will advance three principal objectives with the first objective to provide a complete range of expertise, training, equipment, and data analysis tools to extensively study and characterize the role of cytoskeleton in preclinical models of murine lung injury. We will employ the state-of- the-art techniques to a) characterize the role of cytoskeleton in regulating lung endothelial cell barrier function, b) determine the effects of specific interventions in order to provide insight into the efficacy and mechanisms of novel therapeutic strategies, and c) facilitate the translation of basic research to clinical interventions. Toward this ultimate aim, the Core will first provide validated quantitative measurements of vascular permeability and inflammation. The second objective is to house and care for the genetically-engineered mice utilized in this PPG and to generate novel transgenic and knockout mice (e.g., inducible endothelium conditional knockout mice). The third objective is to examine selective siRNAs or pharmacological agonists or antagonists for cytoskeletal proteins as potential therapeutic strategies and approaches for ARDS and VILI models. The fourth objective will be to provide rigorously performed, protocol-driven performance of specific experimental strategies involving LPS and VILI preclinical models of ARDS/VILI as well as S1P and HGF rescue interventions. The last objective will be to evaluate the function of ARDS-associated SNPs and sites of functional protein post-translational modification (PTM), utilizing mutated cDNA (high efficiency expression plasmids) targeting the lung endothelium (with ACE antibody conjugated liposome) in the endothelial conditional knockout mice. As a centralized and functional core, Core C will perform all mice-related work across all three projects of this program, including generating new strains, breeding and housing of mice, generating preclinical ARDS/VILI models, accessing therapeutic effects of siRNAs and chemicals, performing lung inflammation assessment, and providing tissue samples to individual projects for specific assays (including immunohistochemistry and western blot analysis). In addition to its own space and equipment, the Core will have full access to and will utilize resources available at the University of Arizona shared facilities including the Genetically Engineered Mouse Models Core (GEMM) and the Small Animal Medical Imaging Service (SAMIS) Facility.